Inflammatory bowel disease (IBD) is a growing public health and socio-economic challenge that affects pediatric and adult populations worldwide. However, the pathogenesis of IBD is poorly understood and therapeutic options are limited and often ineffective. Basic and translational studies suggest that IBD is causally-associated with the development of pro-inflammatory CD4+ T cell responses directed against normally beneficial intestinal commensal bacteria. Therefore interrogating the mechanisms that limit pathologic immune responses to commensal bacteria in the context of health and intestinal inflammation will be critical for the development of novel therapeutics to prevent and treat IBD. Recent studies from this and other laboratories have identified a role for populations of innate lymphoid cells (ILCs) in regulating cytokine-mediated immunity, inflammation and tissue repair in the intestine. In recently published and new preliminary data we have identified that group 3 ILCs (ILC3s) also play a critical role in directly limiting the development of pro- inflammatory commensal bacteria-specific CD4+ T cells via major histocompatibility complex class II (MHCII)- dependent interactions (Hepworth et al. Nature, 2013 and Hepworth et al., Science, 2015). Critically, genetic deletion of MHCII in murine ILC3s results in T cell-dependent intestinal inflammation, and pediatric Crohn's disease patient's exhibit reduced MHCII expression on intestinal ILC3s. These findings provoke the central hypothesis that MHCII+ ILC3s critically regulate pro-inflammatory CD4+ T cell responses to commensal bacteria and are essential to maintain tissue homeostasis in the gastrointestinal tract of humans. We will employ these powerful basic and translational approaches to delineate the pathways by which ILC3s regulate pathologic CD4+ T cell responses to commensal bacteria and intestinal inflammation. Two specific aims of this project will determine (i) the cellular and molecular mechanisms by which MHCII+ ILC3s regulate pathologic commensal bacteria-specific CD4+ T cells, and (ii) what regulates ILC3-intrinsic MHCII expression in the healthy and inflamed intestine of mice and humans. Collectively, these studies will systematically interrogate the role and regulation of ILC3-intrinsic MHCII in basic mouse models, and pioneer translational studies examining these pathways in healthy human and IBD patient populations. These studies will inform ongoing efforts to develop effective therapies targeting ILCs to prevent or treat IBD in both children and adults, in addition to multiple other chronic inflammatory diseases associated with dysregulated immune responses to commensal bacteria.